Steroid regulation: An overlooked aspect of tolerance and chronic rejection in kidney transplantation. (15th September 2018)

• Record Type: Journal Article
• Authors: Christakoudi, Sofia; Runglall, Manohursingh; Mobillo, Paula; Rebollo-Mesa, Irene; Tsui, Tjir-Li; Nova-Lamperti, Estefania; Norris, Sonia; Kamra, Yogesh; Hilton, Rachel; Bhandari, Sunil; Baker, Richard; Berglund, David; Carr, Sue; Game, David; Griffin, Sian; Kalra, Philip A.; Lewis, Robert; Mark, Patrick B.; Marks, Stephen D.; Macphee, Iain; McKane, William; Mohaupt, Markus G.; Pararajasingam, Ravi; Kon, Sui Phin; Serón, Daniel; Sinha, Manish; Tucker, Beatriz; Viklický, Ondrej; Lechler, Robert I.; Lord, Graham M.; Stahl, Daniel; Hernandez-Fuentes, Maria P.;
• Is Part Of: Molecular and cellular endocrinology. Volume 473(2018)
• Page Start: 205
• Page End: 216
• Publication Date: 2018-09-15
• Subjects: Steroid receptor genes -- Steroid conversion -- Transplantation -- Kidney -- Tolerance -- Chronic rejection; 11β-HSD 11β-Hydroxysteroid dehydrogenase -- C1s Complement component 1, s subcomponent gene -- CISH Cytokine inducible SH2-containing protein gene -- CNI calcineurin inhibitors -- CR chronic rejection -- CV.AUC cross-validated area under the receiver operating characteristic curve -- CvS comparison between chronic rejection and stable patients -- FOXP3 forkhead box P3 gene -- GAMBIT Genetic Analysis of Molecular Biomarkers of Immunological Tolerance study -- GC glucocorticoid(s) -- GILZ glucocorticoid-induced leucine zipper protein gene -- GR glucocorticoid receptor (NR3C1 gene) -- H6PD hexose-6-phosphate dehydrogenase gene -- HC healthy controls -- HPRT hypoxanthine phosphoribosyltransferase 1 gene -- HSD11B1 and HSD11B2 hydroxysteroid (11-beta) dehydrogenase 1 and 2 genes -- IQR interquartile range -- KTR kidney transplant recipients -- MAPK8 mitogen-activated protein kinase 8 gene -- MR mineralocorticoid receptor (NR3C2 gene) -- NR3C1 nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) gene -- NR3C2 nuclear receptor subfamily 3, group C, member 2 (mineralocorticoid receptor) gene -- PBMC peripheral blood mononuclear cells -- PNOC prepronociceptin gene -- PPIF peptidylprolyl isomerase F gene -- RT-qPCR quantitative real-time reverse transcriptase polymerase chain reaction -- STAT1 signal transducer and activator of transcription 1 gene -- T-reg regulatory T-cells -- TSC22D3 TSC22 domain family, member 3 gene -- TvS comparison between tolerant and stable patients; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2018.01.021
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Steroid conversion ( HSD11B1, HSD11B2, H6PD ) and receptor genes ( NR3C1, NR3C2 ) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor ( NR3C1 ) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene ( NR3C2 ) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation. Highlights: Steroid conversion and receptor genes in blood are altered in kidney transplantation. Steroid activation ( HSD11B1, H6PD ) and response ( NR3C1 ) are not increased in tolerance. Upregulated NR3C1 and HSD11B1 indicate unmet cortisol demand in chronic rejection. Drug-adjusted NR3C1 expression is associated with neutrophils and NR3C2 with T-cells. Drug adjustment enables evaluation of endogenous factors influencing gene expression.